RESEARCH ARTICLE
Development of salivary cortisol circadian rhythm in preterm infants Katrin Ivars1, Nina Nelson1,2, Annette Theodorsson3, Elvar Theodorsson4, Jakob O. Stro¨m4,5, Evalotte Mo¨relius6*
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1 Department of Pediatrics and Department of Clinical and Experimental Medicine, Linko¨ping University, Linko¨ping, Sweden, 2 Department of Quality and Patient Safety, Karolinska University Hospital, Stockholm, Sweden, 3 Department of Neurosurgery and Department of Clinical and Experimental Medicine, Linko¨ping University, Linko¨ping, Sweden, 4 Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linko¨ping University, Linko¨ping, Sweden, 5 Department of Neurology, Faculty of ¨ rebro, O ¨ rebro, Sweden, 6 Division of Nursing Science, Department of Medicine and Health, University of O Social and Welfare Studies, Linko¨ping University, Norrko¨ping, Sweden * [email protected]
Abstract OPEN ACCESS
Objectives
Citation: Ivars K, Nelson N, Theodorsson A, Theodorsson E, Stro¨m JO, Mo¨relius E (2017) Development of salivary cortisol circadian rhythm in preterm infants. PLoS ONE 12(8): e0182685. https://doi.org/10.1371/journal.pone.0182685
To investigate at what age preterm infants develop a salivary cortisol circadian rhythm and identify whether it is dependent on gestational age and/or postnatal age. To evaluate whether salivary cortisol circadian rhythm development is related to behavioral regularity. To elucidate salivary cortisol levels in preterm infants during the first year of life.
Editor: Igor Branchi, Istituto Superiore Di Sanita, ITALY
Methods
Received: January 10, 2017 Accepted: July 21, 2017 Published: August 10, 2017 Copyright: © 2017 Ivars et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper. Funding: This study was supported by the County Council of O¨stergo¨tland, Sweden and Medical Research Council of Southeast Sweden, FORSS (FORSS-8396, FORSS-12268, FORSS-37391, FORSS-78011). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.
This prospective, longitudinal study included 51 preterm infants. 130 healthy full-term infants served as controls. Monthly salivary cortisol levels were obtained in the morning (07:30– 09:30), at noon (10:00–12:00), and in the evening (19:30–21:30), beginning at gestational age week 28–32 and continuing until twelve months corrected age. Behavioral regularity was studied using the Baby Behavior Questionnaire.
Results A salivary cortisol circadian rhythm was established by one month corrected age and persisted throughout the first year. The preterm infants showed a cortisol pattern increasingly more alike the full-term infants as the first year progressed. The preterm infants increase in behavioral regularity with age but no correlation was found between the development of salivary cortisol circadian rhythm and the development of behavior regularity. The time to establish salivary cortisol circadian rhythm differed between preterm and full-term infants according to postnatal age (p = 0.001) and was dependent on gestational age. Monthly salivary cortisol levels for preterm infants from birth until twelve months are presented. Additional findings were that topical corticosteroid medication was associated with higher concentrations of salivary cortisol (p = 0.02) and establishment of salivary cortisol circadian rhythm occurred later in infants treated with topical corticosteroid medication (p = 0.02).
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Cortisol circadian rhythm in preterm infants
Abbreviations: AGA, appropriate for gestational age; BBQ, Baby Behavior Questionnaire; CA, corrected age; CCR, cortisol circadian rhythm; CRIB, Clinical Risk Index for Babies; GA, gestational age; HPA, hypothalamic-pituitaryadrenal; LITE, Life Incidence of Traumatic Events checklist; NICU, neonatal intensive care unit; PNA, postnatal age; SGA, small for gestational age; TCM, topical corticosteroid medication.
Conclusions Salivary cortisol circadian rhythm is established by one month corrected age in preterm infants. Establishment of salivary cortisol circadian rhythm is related to gestational age rather than to postnatal age. Salivary cortisol circadian rhythm development is not related to behavioral regularity.
Introduction Cortisol is considered a major biomarker of stress among children and adults [1, 2]. The fetal hypothalamic-pituitary-adrenal (HPA) system responsible for cortisol release is functional by the beginning of the second trimester [3]. Cortisol is secreted in a pulsatile fashion in a circadian rhythm, peaking in the morning and displaying a nadir in the evening [4], from age one month in healthy full-term infants [5]. To further understand the development of cortisol expression in infants born preterm it is important to investigate when cortisol circadian rhythm (CCR) is established. Seven earlier studies were found investigating the development of CCR in preterm infants [6–12], three of which investigated salivary cortisol [7–9], three investigated plasma cortisol [6, 11, 12] and one serum cortisol [10]. However, there is no consensus regarding when CCR is established or whether it is dependent on gestational age (GA) or postnatal age (PNA). Kidd et al. included infants (n = 11) born before 30 weeks’ gestation and found salivary CCR in single infants but not on a group level and no sustainable CCR was developed during the inclusion period, which were during the hospital stay [7]. Antonini et al. included infants (n = 9) born between 31 and 34 weeks GA and followed them longitudinal from two to 24 weeks of postnatal age. They found that salivary CCR emerged between eight and 12 postnatal weeks [8]. Vermes et al. detected plasma CCR in neonates (n = 5) from the age of 3 months [12]. The remaining four studies did not confirm CCR during the study periods, which varied between one and four postnatal weeks [6, 9–11]. Three studies have investigated factors that may influence development of CCR in infants [5, 11, 13]. Scott et al. found significantly lower cortisol levels in preterm infants requiring respiratory support and/or surfactant treatment. They also investigated CCR dependency on age and found a significant inverse relationship with higher cortisol levels at lower GA [11]. Price et al. found a weak correlation between CCR development and sleep regularity in fullterm infants. Ivars et al. found a stronger CCR and behavior regularity with increasing age in full-term infants but however, no correlation between CCR development and behavior regularity as measured by the Baby Behavior Questionnaire (BBQ) [5, 14]. Trauma and depression have previously been shown to influence the HPA axis in adolescents and adults [15, 16]. But no correlation was found in full-term infants between CCR development and trauma as registered through the Life Incidence of Traumatic Events (LITE) instrument [5]. However, compared to healthy full-term infants, preterm infants are exposed to several stressful events related to intensive care in the neonatal period which, in combination with their immaturity make them more vulnerable and less resistant to additional stressful events such as family trauma. Exposure to stressful events during the neonatal period may affect the development of the HPA axis subsequently leading to altered cortisol levels during childhood [17]. Basal salivary cortisol expression across the first year of life has been found to differ by GA at birth in infants born preterm [18, 19]. Furthermore, Brummelte et al [17] found a similar pattern of cortisol across the day in preterm and full-term children at age 7 years, but a significant difference in level, with preterm infants having higher salivary cortisol levels than full-term infants
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at bedtime. In contrast, Buske-Kirschbaum et al. [20] found that children born preterm had higher awakening cortisol levels than those born full-term at school-age. It is important to study when CCR emerges in infancy in preterm infants, and whether the pattern across the day differs during infancy in preterm infants compared to full-term infants. The aims of the present study were to investigate at what age CCR is established in preterm infants and to identify whether CCR is dependent on GA or PNA. Additional aims were to establish whether development of CCR is related to behavioral regularity and to elucidate salivary cortisol levels during the first year of life in preterm infants. In the present study, a control group of full-term infants was used to compare salivary cortisol levels, CCR development and development of behavior regularity [5, 14].
Materials and methods Participants A convenience sample of 51 preterm infants born at University Hospital in Linko¨ping or at Ryhov Hospital in Jo¨nko¨ping were included in the study. Characteristics of the infants and their parents are compiled in Tables 1 and 2. All parents were healthy, lived together as couples, and the mothers did not use tobacco. The infants were born between GA (week+day) 23+2 and 31+6. They were divided into age groups based on GA at birth: 1000 nmol/L. These outlier values are all included in the statistical analyses but excluded when mean values for salivary cortisol levels during the first year of life is presented.
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Missing data Reasons for missing cortisol samples include: severe illness preventing sampling, one infant died due to severe illness, failure of parents to send samples to hospital, insufficient quantity of saliva, and samples obtained outside allotted time slots. In total, 636 (13.3%) of 4800 samples were missing. The missing evening/morning indexes are marked with an X for each month in Fig 1.
Results On a group level from one month CA, preterm infants developed CCR—defined by significantly higher morning cortisol levels than evening cortisol levels—that persisted throughout the first year of life CA, Fig 2; Table 3. Fig 1 presents individual patterns of CCR development in preterm infants during the first year of life; for reference values from control group see [5]. The following patterns were observed: CCR developed at an early age and persisted each month thereafter; some infants failed to develop a stable pattern, deviating occasional months from CCR at an older age; and some infants failed to develop any CCR during the first year of life, as defined by the cut-off of a 20%-difference. Evening/Morning mean indexes by group were: Preterm infants GA 1000 nmol/L ##
= without two outliers >1000 nmol/L
https://doi.org/10.1371/journal.pone.0182685.t005
Table 6. Number of reported traumas at three different time periods during infants’ first year of life. Number of Traumas (n)
CA Month 1 Number of infants (n)
CA Month 6 Number of infants (n)
CA Month 12 Number of infants (n)
1
6
6
5
2
7
4
0
3
1
0
0
Total:
14
10
5
Corrected age (CA). The traumas were most often hospital-related, which resulted in reported traumas in a larger number of infants at a lower age due to hospitalization for prematurity and birth-related sickness. Trauma was otherwise rare in the group. The most common trauma other than personal hospitalization included hospitalization of a family member (most often mother). https://doi.org/10.1371/journal.pone.0182685.t006
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the first year and is dependent on GA rather than PNA. Moreover, the study presents consecutive salivary cortisol levels for preterm infants from birth until age twelve months CA. Seven earlier studies have investigated development of CCR in preterm infants [6–12]. Regardless of whether the source of cortisol was saliva, plasma, or serum, the results from these studies were either in line with ours regarding time for onset of CCR [8, 12], or were not designed to cover that time period (one month CA) [6, 7, 9–11]. However, most previous studies only report on the first observed CCR age but not what happens later, after the first detected CCR. One strength of the present study is the longitudinal design showing that CCR can develop earlier or later in individuals but that once observed does not mean it is stable. It is known that maturation of the adrenal cortex in preterm infants relates to GA (in infants born before GA week 33) [32]. Low GA in preterm infants is often used to predict perinatal morbidity, delayed maturation of lung function, and state of health, as well as illness and concentration difficulties later in life [33, 34]. Only Scott et al. have previously considered development of CCR in relation to GA or PNA [11]. Their results show an inverse relationship, with higher cortisol levels at lower GA and CCR dependency on GA. Our current results show that CCR develops in preterm infants at one month CA and confirm that CCR is dependent on GA. CCR at one month CA in preterm infants resembles CCR at one month PNA in full-term infants [5]. The present study adds important knowledge on this subject; to our knowledge, it is the most extensive in the literature with regard to sampling regularity, consistency, and duration. An increased regularity (BBQ) developed during the first year of life in preterm infants but no significant correlation was seen between CCR development and regularity either in our preterm material or in full-term infants [5, 14]. Sleep-wake patterns and regularity have previously been studied in relation to CCR development in preterm [8] and full-term infants [5, 13, 14]. Sleep time increased at PNA week eight in both studies, but there was no correlation with CCR. The observed lack of correlation between CCR and behavioral regularity in this and prior study [5, 14] may be because CCR depends on maturity of biological functions such as maturation of the adrenal cortex and other developmental functions that accompany increased GA [32], whereas regularity in behaviors such as sleep seems to be dependent on both GA and environmental influences, e.g. days at home or in hospital care [35]. Due to large inter-individual variations in absolute morning-evening cortisol differences, the Wilcoxon rank-sum test was selected to evaluate the main parameters in the current study as well as in earlier studies [7–9, 30, 31]. Also, several previous studies have corroborated that absolute basal cortisol levels vary substantially both intra-individually and inter-individually [7, 10–12, 19, 36–38], which is why an evening/morning cortisol index for each individual was considered more appropriate when analyzing data from multiple individuals in the current study. It is also well-known that preterm infants have greater variability and higher cortisol levels than healthy full-term infants [7, 10–12, 19, 36, 37]. Except from large individual variations in absolute cortisol levels there were also some extreme outliers in the present study. Two infants were accounted for 78% of the values >1000 nmol/L. One explanation for this could be treatment with TCM. TCM has previously been shown to affect cortisol levels in preterm infants with respiratory diseases [39, 40]. The present study confirms these results, showing higher cortisol levels both morning and evening, and in addition presents new results showing an association between TCM and delayed CCR development. No prior study on CCR development in preterm infants has reported this important finding [6–12], which signals the need for further studies on this matter. No correlation was found between trauma (LITE) and cortisol levels, which is in line with the results on healthy full-term infants [5], but in contrast to another study where multiple traumas in abused adolescents did influence salivary cortisol levels [15]. One plausible
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explanation for this lack of significant correlation may be that most of the infants experienced few traumatic life events other than severe illness and hospitalization. Hospitalization in a NICU often involves separation from the mother that may affect the development of the HPA axis. For instance, parental closeness and skin-to-skin contact increase the co-regulation of salivary cortisol levels between preterm infants in the NICU and their mothers while separation seems to delay such co-regulation [41, 42]. This needs to be further investigated in relation to CCR in future studies.
Limitations There are some limitations with the study; the sample size is more limited than the control group of full-term infants and some infants were too ill at the beginning of the study to be eligible for saliva sampling; a larger population would have contributed to more data regarding cortisol levels in early preterm infants. Another limitation is sampling frequency. Cortisol levels peak in the morning and reach a nadir in the evening. Our sampling times were morning, noon, and evening, but an entire 24-hour cortisol pattern would perhaps have yielded even more information about CCR, especially in hospitalized preterm infants in the NICU environment. Neither did we collect information about the time of awakening in relation to each saliva sampling because of the risk with accuracy of data due to infants’ different sleep patterns and sleep durations during the first year. Instead we focused on the regularity.
Conclusions A salivary cortisol circadian rhythm in preterm infants can be detected—on a group level—at one month corrected age, which is earlier than previous studies have shown. The development of the salivary cortisol circadian rhythm is dependent on gestational age rather than postnatal age. The current study also provides never-before-published data on consecutive salivary cortisol levels in a fairly large population of preterm infants from birth until twelve months corrected age. Topical corticosteroid medication was found to be associated with elevated levels of cortisol and significantly delayed the development of the salivary cortisol circadian rhythm.
Acknowledgments We would like to thank all the infants and parents, as well as the dedicated personnel at the NICUs in both Linko¨ping University Hospital and Ryhov Hospital in Jo¨nko¨ping, who were involved in this study. We especially appreciate the outstanding professionalism of research nurse Christina Fuxin, in collaboration with Dr. Helena Lu¨ning. The following healthcare professionals performed excellent work in recruiting families, teaching parents about saliva sampling, and collecting questionnaires: Marie Hassel, Jane Vanky, and Irja Va¨ina¨mo¨ at Linko¨ping University Hospital, and Karin Fridolfsson, Anna Granath, Maria Stro¨m, Ewa Bolin, and Dr. Fredrik Ingemansson at Ryhov Hospital in Jo¨nko¨ping. Lisbeth Hja¨lle and Anna Pfister are particularly acknowledged for their skilled technical assistance in reliably carrying out laboratory work, especially with RIA analyses. Mats Fredrikson, PhD, was supportive with experienced statistical advice.
Author Contributions Conceptualization: Nina Nelson, Evalotte Mo¨relius. Formal analysis: Katrin Ivars, Elvar Theodorsson, Jakob O. Stro¨m. Funding acquisition: Nina Nelson, Evalotte Mo¨relius.
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Investigation: Katrin Ivars, Nina Nelson, Evalotte Mo¨relius. Methodology: Katrin Ivars, Nina Nelson, Evalotte Mo¨relius. Project administration: Katrin Ivars, Nina Nelson, Evalotte Mo¨relius. Resources: Elvar Theodorsson. Supervision: Nina Nelson, Evalotte Mo¨relius. Validation: Elvar Theodorsson. Visualization: Katrin Ivars, Nina Nelson, Elvar Theodorsson, Jakob O. Stro¨m, Evalotte Mo¨relius. Writing – original draft: Katrin Ivars, Nina Nelson, Evalotte Mo¨relius. Writing – review & editing: Nina Nelson, Annette Theodorsson, Elvar Theodorsson, Jakob O. Stro¨m, Evalotte Mo¨relius.
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Development of salivary cortisol circadian rhythm in preterm infants Katrin Ivars1, Nina Nelson1,2, Annette Theodorsson3, Elvar Theodorsson4, Jakob O. Stro¨m4,5, Evalotte Mo¨relius6*
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1 Department of Pediatrics and Department of Clinical and Experimental Medicine, Linko¨ping University, Linko¨ping, Sweden, 2 Department of Quality and Patient Safety, Karolinska University Hospital, Stockholm, Sweden, 3 Department of Neurosurgery and Department of Clinical and Experimental Medicine, Linko¨ping University, Linko¨ping, Sweden, 4 Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linko¨ping University, Linko¨ping, Sweden, 5 Department of Neurology, Faculty of ¨ rebro, O ¨ rebro, Sweden, 6 Division of Nursing Science, Department of Medicine and Health, University of O Social and Welfare Studies, Linko¨ping University, Norrko¨ping, Sweden * [email protected]
Abstract OPEN ACCESS
Objectives
Citation: Ivars K, Nelson N, Theodorsson A, Theodorsson E, Stro¨m JO, Mo¨relius E (2017) Development of salivary cortisol circadian rhythm in preterm infants. PLoS ONE 12(8): e0182685. https://doi.org/10.1371/journal.pone.0182685
To investigate at what age preterm infants develop a salivary cortisol circadian rhythm and identify whether it is dependent on gestational age and/or postnatal age. To evaluate whether salivary cortisol circadian rhythm development is related to behavioral regularity. To elucidate salivary cortisol levels in preterm infants during the first year of life.
Editor: Igor Branchi, Istituto Superiore Di Sanita, ITALY
Methods
Received: January 10, 2017 Accepted: July 21, 2017 Published: August 10, 2017 Copyright: © 2017 Ivars et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper. Funding: This study was supported by the County Council of O¨stergo¨tland, Sweden and Medical Research Council of Southeast Sweden, FORSS (FORSS-8396, FORSS-12268, FORSS-37391, FORSS-78011). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.
This prospective, longitudinal study included 51 preterm infants. 130 healthy full-term infants served as controls. Monthly salivary cortisol levels were obtained in the morning (07:30– 09:30), at noon (10:00–12:00), and in the evening (19:30–21:30), beginning at gestational age week 28–32 and continuing until twelve months corrected age. Behavioral regularity was studied using the Baby Behavior Questionnaire.
Results A salivary cortisol circadian rhythm was established by one month corrected age and persisted throughout the first year. The preterm infants showed a cortisol pattern increasingly more alike the full-term infants as the first year progressed. The preterm infants increase in behavioral regularity with age but no correlation was found between the development of salivary cortisol circadian rhythm and the development of behavior regularity. The time to establish salivary cortisol circadian rhythm differed between preterm and full-term infants according to postnatal age (p = 0.001) and was dependent on gestational age. Monthly salivary cortisol levels for preterm infants from birth until twelve months are presented. Additional findings were that topical corticosteroid medication was associated with higher concentrations of salivary cortisol (p = 0.02) and establishment of salivary cortisol circadian rhythm occurred later in infants treated with topical corticosteroid medication (p = 0.02).
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Abbreviations: AGA, appropriate for gestational age; BBQ, Baby Behavior Questionnaire; CA, corrected age; CCR, cortisol circadian rhythm; CRIB, Clinical Risk Index for Babies; GA, gestational age; HPA, hypothalamic-pituitaryadrenal; LITE, Life Incidence of Traumatic Events checklist; NICU, neonatal intensive care unit; PNA, postnatal age; SGA, small for gestational age; TCM, topical corticosteroid medication.
Conclusions Salivary cortisol circadian rhythm is established by one month corrected age in preterm infants. Establishment of salivary cortisol circadian rhythm is related to gestational age rather than to postnatal age. Salivary cortisol circadian rhythm development is not related to behavioral regularity.
Introduction Cortisol is considered a major biomarker of stress among children and adults [1, 2]. The fetal hypothalamic-pituitary-adrenal (HPA) system responsible for cortisol release is functional by the beginning of the second trimester [3]. Cortisol is secreted in a pulsatile fashion in a circadian rhythm, peaking in the morning and displaying a nadir in the evening [4], from age one month in healthy full-term infants [5]. To further understand the development of cortisol expression in infants born preterm it is important to investigate when cortisol circadian rhythm (CCR) is established. Seven earlier studies were found investigating the development of CCR in preterm infants [6–12], three of which investigated salivary cortisol [7–9], three investigated plasma cortisol [6, 11, 12] and one serum cortisol [10]. However, there is no consensus regarding when CCR is established or whether it is dependent on gestational age (GA) or postnatal age (PNA). Kidd et al. included infants (n = 11) born before 30 weeks’ gestation and found salivary CCR in single infants but not on a group level and no sustainable CCR was developed during the inclusion period, which were during the hospital stay [7]. Antonini et al. included infants (n = 9) born between 31 and 34 weeks GA and followed them longitudinal from two to 24 weeks of postnatal age. They found that salivary CCR emerged between eight and 12 postnatal weeks [8]. Vermes et al. detected plasma CCR in neonates (n = 5) from the age of 3 months [12]. The remaining four studies did not confirm CCR during the study periods, which varied between one and four postnatal weeks [6, 9–11]. Three studies have investigated factors that may influence development of CCR in infants [5, 11, 13]. Scott et al. found significantly lower cortisol levels in preterm infants requiring respiratory support and/or surfactant treatment. They also investigated CCR dependency on age and found a significant inverse relationship with higher cortisol levels at lower GA [11]. Price et al. found a weak correlation between CCR development and sleep regularity in fullterm infants. Ivars et al. found a stronger CCR and behavior regularity with increasing age in full-term infants but however, no correlation between CCR development and behavior regularity as measured by the Baby Behavior Questionnaire (BBQ) [5, 14]. Trauma and depression have previously been shown to influence the HPA axis in adolescents and adults [15, 16]. But no correlation was found in full-term infants between CCR development and trauma as registered through the Life Incidence of Traumatic Events (LITE) instrument [5]. However, compared to healthy full-term infants, preterm infants are exposed to several stressful events related to intensive care in the neonatal period which, in combination with their immaturity make them more vulnerable and less resistant to additional stressful events such as family trauma. Exposure to stressful events during the neonatal period may affect the development of the HPA axis subsequently leading to altered cortisol levels during childhood [17]. Basal salivary cortisol expression across the first year of life has been found to differ by GA at birth in infants born preterm [18, 19]. Furthermore, Brummelte et al [17] found a similar pattern of cortisol across the day in preterm and full-term children at age 7 years, but a significant difference in level, with preterm infants having higher salivary cortisol levels than full-term infants
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at bedtime. In contrast, Buske-Kirschbaum et al. [20] found that children born preterm had higher awakening cortisol levels than those born full-term at school-age. It is important to study when CCR emerges in infancy in preterm infants, and whether the pattern across the day differs during infancy in preterm infants compared to full-term infants. The aims of the present study were to investigate at what age CCR is established in preterm infants and to identify whether CCR is dependent on GA or PNA. Additional aims were to establish whether development of CCR is related to behavioral regularity and to elucidate salivary cortisol levels during the first year of life in preterm infants. In the present study, a control group of full-term infants was used to compare salivary cortisol levels, CCR development and development of behavior regularity [5, 14].
Materials and methods Participants A convenience sample of 51 preterm infants born at University Hospital in Linko¨ping or at Ryhov Hospital in Jo¨nko¨ping were included in the study. Characteristics of the infants and their parents are compiled in Tables 1 and 2. All parents were healthy, lived together as couples, and the mothers did not use tobacco. The infants were born between GA (week+day) 23+2 and 31+6. They were divided into age groups based on GA at birth: 1000 nmol/L. These outlier values are all included in the statistical analyses but excluded when mean values for salivary cortisol levels during the first year of life is presented.
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Missing data Reasons for missing cortisol samples include: severe illness preventing sampling, one infant died due to severe illness, failure of parents to send samples to hospital, insufficient quantity of saliva, and samples obtained outside allotted time slots. In total, 636 (13.3%) of 4800 samples were missing. The missing evening/morning indexes are marked with an X for each month in Fig 1.
Results On a group level from one month CA, preterm infants developed CCR—defined by significantly higher morning cortisol levels than evening cortisol levels—that persisted throughout the first year of life CA, Fig 2; Table 3. Fig 1 presents individual patterns of CCR development in preterm infants during the first year of life; for reference values from control group see [5]. The following patterns were observed: CCR developed at an early age and persisted each month thereafter; some infants failed to develop a stable pattern, deviating occasional months from CCR at an older age; and some infants failed to develop any CCR during the first year of life, as defined by the cut-off of a 20%-difference. Evening/Morning mean indexes by group were: Preterm infants GA 1000 nmol/L ##
= without two outliers >1000 nmol/L
https://doi.org/10.1371/journal.pone.0182685.t005
Table 6. Number of reported traumas at three different time periods during infants’ first year of life. Number of Traumas (n)
CA Month 1 Number of infants (n)
CA Month 6 Number of infants (n)
CA Month 12 Number of infants (n)
1
6
6
5
2
7
4
0
3
1
0
0
Total:
14
10
5
Corrected age (CA). The traumas were most often hospital-related, which resulted in reported traumas in a larger number of infants at a lower age due to hospitalization for prematurity and birth-related sickness. Trauma was otherwise rare in the group. The most common trauma other than personal hospitalization included hospitalization of a family member (most often mother). https://doi.org/10.1371/journal.pone.0182685.t006
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the first year and is dependent on GA rather than PNA. Moreover, the study presents consecutive salivary cortisol levels for preterm infants from birth until age twelve months CA. Seven earlier studies have investigated development of CCR in preterm infants [6–12]. Regardless of whether the source of cortisol was saliva, plasma, or serum, the results from these studies were either in line with ours regarding time for onset of CCR [8, 12], or were not designed to cover that time period (one month CA) [6, 7, 9–11]. However, most previous studies only report on the first observed CCR age but not what happens later, after the first detected CCR. One strength of the present study is the longitudinal design showing that CCR can develop earlier or later in individuals but that once observed does not mean it is stable. It is known that maturation of the adrenal cortex in preterm infants relates to GA (in infants born before GA week 33) [32]. Low GA in preterm infants is often used to predict perinatal morbidity, delayed maturation of lung function, and state of health, as well as illness and concentration difficulties later in life [33, 34]. Only Scott et al. have previously considered development of CCR in relation to GA or PNA [11]. Their results show an inverse relationship, with higher cortisol levels at lower GA and CCR dependency on GA. Our current results show that CCR develops in preterm infants at one month CA and confirm that CCR is dependent on GA. CCR at one month CA in preterm infants resembles CCR at one month PNA in full-term infants [5]. The present study adds important knowledge on this subject; to our knowledge, it is the most extensive in the literature with regard to sampling regularity, consistency, and duration. An increased regularity (BBQ) developed during the first year of life in preterm infants but no significant correlation was seen between CCR development and regularity either in our preterm material or in full-term infants [5, 14]. Sleep-wake patterns and regularity have previously been studied in relation to CCR development in preterm [8] and full-term infants [5, 13, 14]. Sleep time increased at PNA week eight in both studies, but there was no correlation with CCR. The observed lack of correlation between CCR and behavioral regularity in this and prior study [5, 14] may be because CCR depends on maturity of biological functions such as maturation of the adrenal cortex and other developmental functions that accompany increased GA [32], whereas regularity in behaviors such as sleep seems to be dependent on both GA and environmental influences, e.g. days at home or in hospital care [35]. Due to large inter-individual variations in absolute morning-evening cortisol differences, the Wilcoxon rank-sum test was selected to evaluate the main parameters in the current study as well as in earlier studies [7–9, 30, 31]. Also, several previous studies have corroborated that absolute basal cortisol levels vary substantially both intra-individually and inter-individually [7, 10–12, 19, 36–38], which is why an evening/morning cortisol index for each individual was considered more appropriate when analyzing data from multiple individuals in the current study. It is also well-known that preterm infants have greater variability and higher cortisol levels than healthy full-term infants [7, 10–12, 19, 36, 37]. Except from large individual variations in absolute cortisol levels there were also some extreme outliers in the present study. Two infants were accounted for 78% of the values >1000 nmol/L. One explanation for this could be treatment with TCM. TCM has previously been shown to affect cortisol levels in preterm infants with respiratory diseases [39, 40]. The present study confirms these results, showing higher cortisol levels both morning and evening, and in addition presents new results showing an association between TCM and delayed CCR development. No prior study on CCR development in preterm infants has reported this important finding [6–12], which signals the need for further studies on this matter. No correlation was found between trauma (LITE) and cortisol levels, which is in line with the results on healthy full-term infants [5], but in contrast to another study where multiple traumas in abused adolescents did influence salivary cortisol levels [15]. One plausible
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explanation for this lack of significant correlation may be that most of the infants experienced few traumatic life events other than severe illness and hospitalization. Hospitalization in a NICU often involves separation from the mother that may affect the development of the HPA axis. For instance, parental closeness and skin-to-skin contact increase the co-regulation of salivary cortisol levels between preterm infants in the NICU and their mothers while separation seems to delay such co-regulation [41, 42]. This needs to be further investigated in relation to CCR in future studies.
Limitations There are some limitations with the study; the sample size is more limited than the control group of full-term infants and some infants were too ill at the beginning of the study to be eligible for saliva sampling; a larger population would have contributed to more data regarding cortisol levels in early preterm infants. Another limitation is sampling frequency. Cortisol levels peak in the morning and reach a nadir in the evening. Our sampling times were morning, noon, and evening, but an entire 24-hour cortisol pattern would perhaps have yielded even more information about CCR, especially in hospitalized preterm infants in the NICU environment. Neither did we collect information about the time of awakening in relation to each saliva sampling because of the risk with accuracy of data due to infants’ different sleep patterns and sleep durations during the first year. Instead we focused on the regularity.
Conclusions A salivary cortisol circadian rhythm in preterm infants can be detected—on a group level—at one month corrected age, which is earlier than previous studies have shown. The development of the salivary cortisol circadian rhythm is dependent on gestational age rather than postnatal age. The current study also provides never-before-published data on consecutive salivary cortisol levels in a fairly large population of preterm infants from birth until twelve months corrected age. Topical corticosteroid medication was found to be associated with elevated levels of cortisol and significantly delayed the development of the salivary cortisol circadian rhythm.
Acknowledgments We would like to thank all the infants and parents, as well as the dedicated personnel at the NICUs in both Linko¨ping University Hospital and Ryhov Hospital in Jo¨nko¨ping, who were involved in this study. We especially appreciate the outstanding professionalism of research nurse Christina Fuxin, in collaboration with Dr. Helena Lu¨ning. The following healthcare professionals performed excellent work in recruiting families, teaching parents about saliva sampling, and collecting questionnaires: Marie Hassel, Jane Vanky, and Irja Va¨ina¨mo¨ at Linko¨ping University Hospital, and Karin Fridolfsson, Anna Granath, Maria Stro¨m, Ewa Bolin, and Dr. Fredrik Ingemansson at Ryhov Hospital in Jo¨nko¨ping. Lisbeth Hja¨lle and Anna Pfister are particularly acknowledged for their skilled technical assistance in reliably carrying out laboratory work, especially with RIA analyses. Mats Fredrikson, PhD, was supportive with experienced statistical advice.
Author Contributions Conceptualization: Nina Nelson, Evalotte Mo¨relius. Formal analysis: Katrin Ivars, Elvar Theodorsson, Jakob O. Stro¨m. Funding acquisition: Nina Nelson, Evalotte Mo¨relius.
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Investigation: Katrin Ivars, Nina Nelson, Evalotte Mo¨relius. Methodology: Katrin Ivars, Nina Nelson, Evalotte Mo¨relius. Project administration: Katrin Ivars, Nina Nelson, Evalotte Mo¨relius. Resources: Elvar Theodorsson. Supervision: Nina Nelson, Evalotte Mo¨relius. Validation: Elvar Theodorsson. Visualization: Katrin Ivars, Nina Nelson, Elvar Theodorsson, Jakob O. Stro¨m, Evalotte Mo¨relius. Writing – original draft: Katrin Ivars, Nina Nelson, Evalotte Mo¨relius. Writing – review & editing: Nina Nelson, Annette Theodorsson, Elvar Theodorsson, Jakob O. Stro¨m, Evalotte Mo¨relius.
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